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Kynureninase

From Wikipedia, the free encyclopedia
kynureninase
Crystal structure of Homo sapiens kynureninase.[1]
Identifiers
EC no.3.7.1.3
CAS no.9024-78-6
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
KYNU
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesKYNU, KYNUU, kynureninase, VCRL2
External IDsOMIM: 605197; MGI: 1918039; HomoloGene: 2925; GeneCards: KYNU; OMA:KYNU - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001032998
NM_001199241
NM_003937

NM_027552
NM_001289593
NM_001289594
NM_001398676

RefSeq (protein)

NP_001028170
NP_001186170
NP_003928

NP_001276522
NP_001276523
NP_081828
NP_001385605

Location (UCSC)Chr 2: 142.88 – 143.06 MbChr 2: 43.45 – 43.57 Mb
PubMed search[4][5]
Wikidata
View/Edit HumanView/Edit Mouse

Kynureninase or L-Kynurenine hydrolase (KYNU) (EC 3.7.1.3) is a PLP dependent enzyme that catalyses the cleavage of kynurenine (Kyn) into anthranilic acid (Ant). It can also act on 3-hydroxykynurenine (to produce 3-hydroxyanthranilate) and some other (3-arylcarbonyl)-alanines. Humans express one kynureninase enzyme that is encoded by the KYNU gene located on chromosome 2.[6][7]

KYNU is part of the pathway for the catabolism of Trp and the biosynthesis of NAD cofactors from tryptophan (Trp).

Kynureninase catalyzes the following reaction:

L-kynurenine + H2O ↔ anthranilate + L-alanine

Structure

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Kynureninase belongs to the class V group of aspartate aminotransferase superfamily of structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes. To date, two structures of human kynureninase have determined by X-ray diffraction with resolutions of 2.0 and 1.7 Å.[1][8] Forty percent of the amino acids are arranged in an alpha helical and twelve percent are arranged in beta sheets. Docking of the kynurenine substrate into the active site suggests that Asn-333 and His-102 are involved in substrate binding.[1]

Function

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In KYNU reaction, PLP facilitates Cβ-Cγ bond cleavage. The reaction follows the same steps as the transamination reaction but does not hydrolyze the tautomerized Schiff base. The proposed reaction mechanism involves an attack of an enzyme nucleophile on the carbonyl carbon (Cγ) of the tautomerized 3hKyn-PLP Schiff base. This is followed by Cβ-Cγ bond cleavage to generate an acyl-enzyme intermediate together with a tautomerized Ala-PLP adduct. Hydrolysis of the acyl-enzyme then yields 3hAnt.

The KYNU's reaction mechanism.
The color scheme is as follows: KYNU, PLP, substrate names, inorganic molecules, 3hAn's moiety, Ala's moiety

References

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  1. ^ a b c PDB: 2HZP​; Lima S, Khristoforov R, Momany C, Phillips RS (March 2007). "Crystal structure of Homo sapiens kynureninase". Biochemistry. 46 (10): 2735–44. doi:10.1021/bi0616697. PMC 2531291. PMID 17300176.
  2. ^ a b c GRCh38: Ensembl release 89: ENSG00000115919Ensembl, May 2017
  3. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026866Ensembl, May 2017
  4. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  6. ^ Alberati-Giani D, Buchli R, Malherbe P, Broger C, Lang G, Köhler C, Lahm HW, Cesura AM (July 1996). "Isolation and expression of a cDNA clone encoding human kynureninase". Eur. J. Biochem. 239 (2): 460–8. doi:10.1111/j.1432-1033.1996.0460u.x. PMID 8706755.
  7. ^ Toma S, Nakamura M, Toné S, Okuno E, Kido R, Breton J, Avanzi N, Cozzi L, Speciale C, Mostardini M, Gatti S, Benatti L (May 1997). "Cloning and recombinant expression of rat and human kynureninase". FEBS Lett. 408 (1): 5–10. doi:10.1016/S0014-5793(97)00374-8. PMID 9180257. S2CID 36265922.
  8. ^ PDB: 3E9K​; Lima S, Kumar S, Gawandi V, Momany C, Phillips RS (January 2009). "Crystal structure of the Homo sapiens kynureninase-3-hydroxyhippuric acid inhibitor complex: insights into the molecular basis of kynureninase substrate specificity". J. Med. Chem. 52 (2): 389–96. doi:10.1021/jm8010806. PMID 19143568.

Further reading

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  • PDBe-KB provides an overview of all the structure information available in the PDB for Human Kynureninase